Summary: Researchers have identified a previously undescribed genetic syndrome caused by a homozygous mutation in the SPAG9 gene that affects both brain development and later neurodegeneration. The team linked this mutation to intellectual disability, early speech delays and a pattern of progressive cognitive decline, alongside structural and functional disruptions visible on neuroimaging.
Magnetic resonance imaging and other scans revealed a range of abnormalities, including reduced head size (microcephaly), hippocampal malrotation, iron deposition and progressive cerebral and cerebellar atrophy. These findings expand our understanding of how a single genetic defect can produce both developmental and degenerative neurological consequences and point toward new directions for future research and therapeutic exploration.
Key Facts:
- A homozygous SPAG9 gene mutation (stop-codon deletion) underlies a syndrome with both neurodevelopmental and neurodegenerative features.
- Clinical presentation includes intellectual disability, delayed speech development, cataracts in some cases, and signs suggesting later cognitive deterioration.
- Neuroimaging demonstrated a heterogeneous pattern of brain changes such as microcephaly, hippocampal malrotation, corpus callosum alterations, iron accumulation, and progressive brain atrophy.
Source: Genomic Press
A new genetic syndrome that links neurodevelopmental defects with neurodegeneration
A multidisciplinary team led by investigators at the University of Antioquia reports a novel neurodevelopmental-neurodegenerative syndrome associated with a homozygous deletion in the SPAG9 gene. Their peer-reviewed study, published in Genomic Psychiatry, describes the clinical, imaging and genetic evidence connecting this SPAG9 alteration to a distinctive and progressive neurological disorder.
The researchers followed a Colombian family for more than ten years and closely monitored three affected siblings. Their study combined detailed clinical evaluations, genetic sequencing and repeated neuroimaging to document the syndrome’s onset, variability and long-term course.
Principal findings highlighted by the authors include:
1. Identification of a homozygous deletion in SPAG9 (described as c.2742del, p.Tyr914Ter) that cosegregates with the disorder in the family studied.
2. Comprehensive clinical profiling showing a consistent pattern of intellectual disability, delayed speech, ocular findings such as cataracts in some individuals, and cerebellar signs affecting coordination.
3. Evidence of progressive cognitive decline over years of follow-up, supporting an active neurodegenerative component beyond the initial developmental impairment.
4. Diverse neuroimaging abnormalities that varied between siblings but collectively included microcephaly, hippocampal malrotation, structural changes in the corpus callosum, focal iron deposition in deep brain structures, and both cerebral and cerebellar atrophy evolving over time.
Dr. Natalia Acosta-Baena, the study’s lead author, emphasizes the importance of this discovery: “This mutation gives us a rare opportunity to observe how a single genetic change can shape early brain development and also compromise neuronal integrity later in life. That dual effect is central to understanding many neurological conditions that blur the lines between developmental and degenerative processes.”
Senior author Dr. Carlos Andrés Villegas-Lanau notes that the syndrome may serve as a model for examining how disruptions in intracellular transport compromise neuronal health: “SPAG9 appears to be involved in critical cellular transport pathways. Disruption of retrograde axonal transport, for example, can interrupt essential signaling and clearance systems in neurons, which could explain both developmental defects and later degeneration.”
SPAG9 had not been previously implicated in human brain disorders. The authors propose that the identified stop-codon deletion likely produces a loss of normal SPAG9 function, with downstream effects on axonal transport and neuronal survival. While the precise molecular cascade remains to be defined, the observational and imaging data provide a clear link between the genetic lesion and the clinical phenotype.
The longitudinal nature of the study strengthens its conclusions. By tracking affected individuals from childhood into adulthood, the team documented symptom evolution, variability between siblings, and the progressive nature of cognitive and structural decline. Such long-term clinical datasets are uncommon in genetic research and add valuable context to genotype–phenotype correlations.
The researchers call for further studies to clarify the molecular mechanisms by which SPAG9 deficiency produces neurologic dysfunction and to explore targeted interventions. While therapeutic strategies remain speculative at this stage, identifying SPAG9 as a critical gene for both brain development and maintenance opens avenues for basic and translational research aimed at protecting neuronal function.
About this genetics, neurodevelopment, and neurodegeneration research news
Author: Ma-Li Wong
Source: Genomic Press
Contact: Ma-Li Wong – Genomic Press
Image: The image is credited to Neuroscience News
Original Research: Open access. “A novel neurodevelopmental-neurodegenerative syndrome that cosegregates with a homozygous SPAG9/JIP4 stop-codon deletion” by Carlos Andrés Villegas-Lanau et al., published in Genomic Psychiatry.